title: β-mannosylceramide activates type I natural killer t cells to induce tumor immunity without inducing long-term functional anergy.
abstract: OBJECTIVE
  Most studies characterizing antitumor properties of invariant natural killer T (iNKT) cells have used the agonist, α-galactosylceramide (α-GalCer). However, α-GalCer induces strong, long-lasting anergy of iNKT cells, which could be a major detriment for clinical therapy. A novel iNKT cell agonist, β-mannosylceramide (β-ManCer), induces strong antitumor immunity through a mechanism distinct from that of α-GalCer. The objective of this study was to determine whether β-ManCer induces anergy of iNKT cells.
  
  
  METHODS
  Induction of anergy was determined by ex vivo analysis of splenocytes from mice pretreated with iNKT cell agonists as well as in the CT26 lung metastasis in vivo tumor model.
  
  
  RESULTS
  β-ManCer activated iNKT cells without inducing long-term anergy. The transience of anergy induction correlated with a shortened duration of PD-1 upregulation on iNKT cells activated with β-ManCer, compared with α-GalCer. Moreover, whereas mice pretreated with α-GalCer were unable to respond to a second glycolipid stimulation to induce tumor protection for up to 2 months, mice pretreated with β-ManCer were protected from tumors by a second stimulation equivalently to vehicle-treated mice.
  
  
  CONCLUSIONS
  The lack of long-term functional anergy induced by β-ManCer, which allows for a second dose to still give therapeutic benefit, suggests the strong potential for this iNKT cell agonist to succeed in settings where α-GalCer has failed.
authors.affiliation: Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: O'Konek
authors.forename: Shingo
authors.initials: S
authors.lastname: Kato
authors.forename: Satomi
authors.initials: S
authors.lastname: Takao
authors.forename: Liat
authors.initials: L
authors.lastname: Izhak
authors.forename: Zheng
authors.initials: Z
authors.lastname: Xia
authors.forename: Petr
authors.initials: P
authors.lastname: Illarionov
authors.forename: Gurdyal S
authors.initials: GS
authors.lastname: Besra
authors.forename: Masaki
authors.initials: M
authors.lastname: Terabe
authors.forename: Jay A
authors.initials: JA
authors.lastname: Berzofsky
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002518:Ceramides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D017635:Clonal Anergy / Q000187:drug effects* / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D005699:Galactosylceramides / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D051379:Mice; D055611:Natural Killer T-Cells / Q000187:drug effects* / Q000276:immunology*; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism
chemical_list: D002518:Ceramides; D005699:Galactosylceramides; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; C493154:alpha-galactosylceramide